QT interval prolongation and cardiotoxicity in shorter regimens for rifampicin-resistant tuberculosis

OBJECTIVES: Effective rifampicin-resistant tuberculosis (RR-TB) regimens often include multiple QT-prolonging drugs, necessitating evaluation across different combinations. METHODS: Using pooled electrocardiogram data from two trials, three QT-prolonging shorter regimens for RR-TB were studied: the injectable-containing regimen comprising moxifloxacin and clofazimine (Mfx/Cfz), a levofloxacin-based regimen with clofazimine (Lfx/Cfz), and a bedaquiline-containing regimen with clofazimine (Bdq/Cfz). The prevalence and severity of corrected QT interval (QTc) prolongation between regimens were compared, and risk factors were evaluated. RESULTS: Among 410 RR-TB participants, significant QTc prolongation was reported in 48.4% (78/161) of participants receiving the Mfx/Cfz regimen, 31.1% (51/164) receiving the Lfx/Cfz regimen, and 34.1% (29/85) receiving the Bdq/Cfz regimen. Nearly half of the significant QTc prolongation events occurred within 4 months of treatment. Seven episodes of symptomatic arrhythmia were documented. Compared with the Lfx/Cfz regimen, the Mfx/Cfz regimen was associated with an increased risk of significant QTc prolongation (adjusted hazard ratio 1.45, 95% confidence interval 1.01-2.07, P = 0.044). Additionally, pre-existing thyroid disease, cavitation, and older age were identified as independent risk factors of significant QTc prolongation. CONCLUSION: The Mfx/Cfz combination was associated with an elevated risk of QTc prolongation. Close electrocardiogram monitoring throughout the entire treatment course is advised in patients receiving such combination.